Is CA8 p.Pro14Arg (c.41C>G) pathogenic?

CA8 p.Pro14Arg (c.41C>G) is classified Uncertain significance in CA8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-27). AlphaMissense: likely benign (0.1045); Ultra-rare (popmax 0.0124%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CA8 p.Pro14Arg (c.41C>G)?

CA8 p.Pro14Arg (c.41C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CA8 p.Pro14Arg (c.41C>G) in the general population?

CA8 p.Pro14Arg (c.41C>G) is ultra-rare (popmax 0.0124%, nfe) (gnomAD).

What do computational predictors say about CA8 p.Pro14Arg (c.41C>G)?

AlphaMissense predicts likely benign (score 0.1045) — an in-silico prediction, not a clinical call.

CA8 p.Pro14Arg

c.41C>G · rs746415479 · VCV1335712

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1045 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1045	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.24 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0124% European (non-Finnish) · 146/1,176,096 alleles

Filtering AF 0.0107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00917% 147/1,603,084 alleles · ultra-rare exomes 145/1,450,900 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0124%	8,055
African / African-American	0.00134%	74,580

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CA8
Protein: p.Pro14Arg
Coding: c.41C>G
MANE Select: NM_004056
dbSNP: rs746415479
Type: single nucleotide variant
Location: chr8:60281107 (GRCh38)
Gene constraint: LOEUF 0.698 · pLI 0.24 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.51 · 1 PDB
Residue 14: the 'disordered' region

Full CA8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CA8 p.Pro14= Benign ★ same residue
CA8 p.Ser71Phe Uncertain significance ★★ ⚠ same condition
CA8 c.576+5G>A Benign/Likely benign ★★ same condition
CA8 p.Glu109= Benign ★★ same condition
CA8 p.Glu22= Benign ★★ same condition
CA8 p.Gly265= Benign/Likely benign ★★ same condition
CA8 p.Leu112= Benign ★★ same condition
CA8 p.Pro103= Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ca8-p-pro14arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown